Epigenome-microbiome interplay in early life associates with infants’ neurodevelopmental outcomes

Epigenetic regulation and microbiome maturation are sensitive to perinatal cues. We studied early-life disruptions in the host epigenome and microbial colonization in relation to neurodevelopmental disorders. In a longitudinal birth cohort, we analyzed 571 cord blood methylomes and 5,328 gut metagenomes from infants and their parents across 969 families to unravel microbiome-epigenome interactions in neuro-immune pathways. We found that Caesarean-section delivery was associated with differential methylation of genes involved in immune responses and neural development. It also reduced vertical maternal microbiome transmission, partially compensated by the paternal microbiome. Children with hypermethylated genes involved in neurogenic and neurotransmission pathways in cord blood showed higher autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) scores at age 3. However, these epigenetic effects were mitigated by early colonization of Lachnospira pectinoschiza in ASD and Parabacteroides distasonis in ADHD. These findings highlight early-life epigenetic regulation and microbiome-dependent mechanisms in the developmental origins of neurodevelopmental disorders.